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Role of Kidney in Primary

Hypertension
Dr. Anuradha
Consultant Nephrologist
Sunshine Hospitals
Secunderabad
Epidemiology of Hypertension (HTN)

2000 : 1 billion adults (> 25 % of the worlds population) had HTN

2012: In India, 23.10% men and 22.60% women over 25 years old suffer from
HTN (WHO)

2025 : HTN cases will increase to 1.56 billion.

Primary HTN accounts for 90-95 % of all cases of HTN

Indian J Med Res 128, December 2008, pp 688-690


Progression of Essential Hypertension

20-40 years: Early


HTN (in which
10-30 years : Prehypertension 30-50 years: 40-60 years:
increased peripheral
(by increased cardiac output) Established HTN Complicated HTN
resistance is
prominent)
50
41.9
40.3 41.4
38.5

Percent of Population
40 37.5 38.2

30.3
27.0 27.6
30 27.8 25.4 26.4
26.9 24.8
25.6 23.7 25.0
22.9

20

10

0
NH White NH White NH Black NH Black Mexican Mexican
Men Women Men Women American American
Men Women

1988-94 1999-02 2003-06

Age-adjusted prevalence trends for high blood pressure in Adults age


20 and older by race/ethnicity, sex and survey (NHANES: 1988-94,
1999-02 and 2003-06). Source: NCHS and NHLBI. NH- non-Hispanic.
Indian Scenario

Hypertension is directly responsible for


57% of all stroke deaths
24% of all coronary heart disease deaths in India.
Hypertension is a controllable disease

2 mmHg population-wide decrease in BP can prevent


151,000 strokes
153,000 coronary heart disease deaths.
J Hypertens 2000; 18(Suppl 1): S3S6.
Epidemiology of Hypertension in India
from 1950s and 1960s (BP >160/95)

1950s 1975 1985 1997

13.1% in
4.35% in Agra 15.52% in Bombay 10.99% in Jaipur Chandigarh

1.2-4 % 6.43% in Rohtak 14.08% in Ludhiana 11.59% in Delhi

1961 1980 1995 1999


Trends in HTN Epidemiology in India
First author Year Age group Place Sample size Prevalence (%)
Men Women Men Women
Urban
Gupta R13 1995 2075 Jaipur 1415 797 29.5 33.5
Gupta PC14 1999 1860 Mumbai 40067 59522 43.8 44.5
Joseph A15 2000 2089 Trivandrum 76 130 31.0 41.2
Anand MP18 2000 3060 Mumbai 1521 141 34.1a
Mohan V16 2001 2070 Chennai 518 657 14.0a
Gupta R17 2002 2075 Jaipur 550 573 36.4 37.5

Rural
Gupta R19 1994 2075 Rajasthan 1982 1166 23.7 16.9
Malhotra P20 1999 1670 Haryana 2559 3.0 5.8b

Journal of Human Hypertension (2004) 18, 7378.


Age-specific
hypertension
prevalence (%) in
an urban Indian
population in the
years 1995 and
2002

Journal of Human Hypertension (2004) 18, 7378.


Frederick Akbar Mahomed, in 1872, as a
medical resident at Guy's Hospital in London,
measured BP in the general population.
Working with a watchmaker, he made a
spring-based device that could measure the
tension of the radial pulse, a portable version
of the sphygmograph invented by tienne-
Jules Marey a decade earlier in France.
While it was known that patients with kidney
disease and albuminuria could have high BP,
he discovered a subset of the population
that had high pressures in the absence of
proteinuria

Discovery of Essential
Hypertension
Historical Timeline of HTN

1872 1905 1911


Frederick Akbar Mahomed Korotkoff describes Janeway and Cushing define
measures BP with auscultatory technique for 160 mm Hg as HTN in >65 yrs
Sphygmograph diastolic BP

Scipione Riva-Rocci invented


BP cuff and mercury Insurance companies recognize Cut-off of 140/90 defined as
manometer HTN associated with mortality HTN

1896 1906 1914


Historical Perspective of Kidney in HTN

1835 1970s
Richard Bright Arthur Guyton
Abnormalities in urine production lead to increased SVR, HTN and Hypothesized that kidney controls BP by regulation of ECV
cardiac hypertrophy Pressure Natriuresis

Harry Goldblatt
Induced malignant HTN in dogs by clipping renal arteries

1930s

J Clin Invest. 2014;124(6):23412347.


1 2 3 4
Cross-transplantation Tx of a kidney from a Dahl Reciprocal transplantation Defect in sodium
studies hypertensive rat into a of kidney from a excretion by the kidney
normotensive, salt- normotensive, salt- confers susceptibility to
resistant recipient resistant animal into a elevated blood pressure.
hypertension in recipient Dahl salt-sensitive rat
regardless of salt intake abrogates hypertension

Hypertension follows the Kidney?


Renal cross-transplantation studies in Dahl rats showing that the trait of salt sensitivity does not
always follow the kidney.

R. Curtis Morris, Jr. et al. Circulation. 2016;133:881-893

Copyright American Heart Association, Inc. All rights reserved.


Renal Abnormalities in Primary
Hypertension
Renal Findings in Primary HTNFindings in
Primary HTN
Most cases have high SVR with relatively normal cardiac
output
Thickening and scarring (arteriolosclerosis) and
constriction of arterioles
Proteinaceous debris in the subendothelial space
(hyalinosis)
Low renal blood flow

Relatively preserved GFR for decades

Reduced ratio of effective renal blood flow to functional


tubular mass, indicating relative renal ischemia
Interstitial inflammatory response

Am J Pathol 34: 685715, 1958.


Hypertension and Salt Sensitivity
A Disease of the Kidney
A timeline of salt and HTN

1872 1957 1963 1970s 1991


Role of salt in HTN Chlorthiazide for Rx HTN due to failure Cross Decreased salt
suspected of HTN (Wilkins) to excrete salt transplantation handling with aging
(Johnson) (Borst) studies in rats (Weinberger)
(Dahl)

No salt diet of
Experiments suggest Impaired pressure Yanomamo Indians
Salt restriction used role for salt in HTN natriuresis in protective against
to treat HTN (Allen) (Dahl) HTN(Guyton) HTN (Oliver)

1922 1960 1969 1975


Interaction of the Modern Western Diet and the Kidneys in the Pathogenesis of Primary
Hypertension

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Molecular Mechanisms Implicated in the Retention of Sodium and Loss of Potassium by the
Kidneys in Primary Hypertension

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Effects of Mineralocorticoids plus a High-Sodium Diet or a High-Sodium and Low-Potassium
Diet Alone in Laboratory Animals

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Molecular Pathways Implicated in the Generation of Increased Arterial and Arteriolar Smooth-
Muscle Tone by an Excess of Sodium and a Deficit of Potassium in Primary Hypertension

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Molecular Pathways Implicated in Potassium-Induced, Endothelium-Dependent Vasodilatation

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Molecular Pathways Implicated in the Central Effects of Sodium and Potassium on Blood
Pressure

Adrogu H, Madias N. N Engl J Med 2007;356:1966-1978


Genetic Mechanisms
Renal Abnormalities in Primary Hypertension
Role of Genes in Primary Hypertension
Genetic polymorphisms that modulate salt excretion may play key role in
some renal causes of HTN
Liddles Syndrome : Activation of ENaC of collecting duct
Syndrome of Apparent Mineralocorticoid Excess
Glucocorticoid-remediable aldosteronism
Genetic defects leading to salt wasting cause hypotension
Bartter's syndrome: Na-K-2Cl transporter (SLC12A1)
Gitelmans Syndrome: Na-Cl cotransporter (SLC12A3)
Genetic polymorphisms in renal sodium handling were found to influence
the frequency of hypertension in the Framingham Heart Study
Contribution of such polymorphisms may be small in Primary HTN

Nature Reviews Genetics 7, 829-840


Genetic Approaches in Primary Hypertension
Candidate gene approaches
angiotensinogen
endothelial nitric oxide synthase
Genome-wide association studies (GWAS)
Nongenetic mechanisms may be more important.
A study of 635 identical twins reported that 60% of twins that were
hypertensive had a twin that was normotensive

Am J Hum Genet. 1994 Sep; 55(3): 566573.


Figure 2. Incidence of hypertension according to (from left to right) ACE genotype in all
subjects, in carriers of the ADD1 460Trp allele, in CC homozygotes of CYP11B2 gene, and
carriers of the ADD1 460Trp allele.

Cristina Barlassina et al. JASN 2002;13:S155-S164

2002 by American Society of Nephrology


Congenital reduction in the
number of nephrons.
Brenners Hypothesis
Nephron Endowment and HTN
Increased frequency of HTN in
adults born with low birth
weight
LBW babies have fewer
nephrons at birth
Brenner suggested low nephron
number predisposes to HTN
Low nephron number can only
explain 20% of those with
hypertension

Am J Hypertens. 1988 Oct;1(4 Pt 1):335-47


Factors
influencing
nephron
endowment.

Pediatr Nephrol. 2011 Sep;26(9):1529-33.


How
decreased
nephron
number
leads to HTN

Am J Hypertens (1988) 1:33547


Acquired renal injury
Timeline of microvascular injury and HTN

1898 1934 1947 1993


Injection of renin Ischemia causes HTN HTN may be a disease Aging causes damage
extract cause high BP (Goldblatt) of renal similar to Ang II and
(Tigerstedt) microvasculature Phenylephrine models
(Goldblatt) (Thomas )

HTN not fully reversible


Autopsy in patients in Goldblatt dog model Cyclosporine causes 40 % cases of Primary
with HTN showed after permanent renal renal microvascular HTN have hyperactive
arteriosclerosis injury (Wilson) injury and HTN (Curtis) SNS (Julius)

1925 1941 1988 1994

N Engl J Med 2002; 346:913-923


Development of Salt-Sensitive Hypertension in Rats after
Exposure to Angiotensin II.

Johnson RJ et al. N Engl J Med 2002;346:913-923.


Focal Microvascular and Tubulointerstitial Injury Induced by
Angiotensin II Infusion in Rats.

Johnson RJ et al. N Engl J Med 2002;346:913-923.


A Pathway for the Development of Salt-Sensitive Hypertension.

Johnson RJ et al. N Engl J Med 2002;346:913-923.


ACQUIRED HEMODYNAMIC
CHANGES IN THE KIDNEY
INTRARENAL ACTIVATION OF VASOCONSTRICTOR SYSTEMS WITH SODIUM
REABSORPTION
Vasoconstrictors and HTN
Sine qua non of hypertension is renal vasoconstriction, primarily of the
preglomerular vasculature
mediated by an imbalance in intrarenal vasoconstrictors and vasodilators
increased intrarenal oxidative stress
a decrease in local endothelial nitric oxide
activation of the renal sympathetic nervous system (SNS)higher
norepinephrine levels
Salt-sensitive hypertension : suppression of the RAS due to sodium and
volume retention
PRA is often not fully suppressed, suggesting some continued activation of
the systemic RAS
Activation of the intrarenal RAS important

https://doi.org/10.1152/ajpregu.00250.2005
Role of intrarenal mineralocorticoid axis
Activation of mineralocorticoid receptor despite suppressed
Aldosterone levels
Leads to inappropriate sodium retention
Activation of the mineralocorticoid receptor may be secondary to
Rac1
Rac1 is a member of the Rho-guanine triphosphate hydroxylase family
Activates the mineralocorticoid receptor via an aldosterone-independent
mechanism in the Dahl salt-sensitive, but not in the salt-resistant rat.

J Clin Invest. 2011 Aug;121(8):3233-43


Plasma and renal angiotensin II concentrations in salt-sensitive hypertension induced with
transient l-NAME administration.

Richard J. Johnson et al. Am J Physiol Renal Physiol


2015;308:F167-F178

2015 by American Physiological Society


ACQUIRED INFLAMMATORY
CHANGES IN THE KIDNEY
INFLAMMATION AS A MECHANISM FOR DRIVING RENAL VASOCONSTRICTION
AND SODIUM RETENTION
Role of Inflammatory Mechanisms
persistent intrarenal oxidative stress and increased intrarenal
angiotensin II activity affects BP
T cells and macrophages involved
MMF blocks Ang II induced HTN in animal models
Normally functioning thymus necessary for the chronic elevation of
BP
Adoptive transfer of T cells restores the hypertensive response to
angiotensin II that was absent in mice strains devoid of lymphocytes

Kidney Int. 2001 Jun;59(6):2222-32.


Could primary hypertension be an
autoimmune disease?
T cells may react to neoantigens expressed in ischemic tissue,
resulting in an autoimmune response
-ketoaldehydes (isoketals) induced by lipid peroxidation can activate
T cells
Patients with primary hypertension have both T cell reactivity and
antibodies to HSP-70 as well as isoketal-modified proteins in
circulating monocytes and dendritic cells
MMF can reduce BP in hypertensive subjects suffering from psoriasis
and rheumatoid arthritis
Low CD4 counts in RVD associated with lower prevalence of HTN

J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S218-25.


Role of obesity and metabolic
syndrome in hypertension
Role of Obesity
6575% of primary hypertension today may be accounted for by
obesity
Impaired natriuresis and salt retention
Hyperuricemia associated with vasoconstriction and interstitial
inflammation
Activation of the SNS
coexistent obstructive sleep apnea
impaired baroreflex sensitivity
Hyperinsulinemia
alterations in adiponectin or leptin.
Interaction among genetic and environmental factors in the development of hypertension.

Oscar A. Carretero, and Suzanne Oparil Circulation.


2000;101:329-335

Copyright American Heart Association, Inc. All rights reserved.


Proposed mechanism for the development of hypertension.

Richard J. Johnson et al. Am J Physiol Renal Physiol


2015;308:F167-F178

2015 by American Physiological Society


Additive effect of hypertensinogenic factors (hatched areas) such as obesity and alcohol intake
on hereditary systolic (white areas) and diastolic BP (black areas).

Oscar A. Carretero, and Suzanne Oparil Circulation.


2000;101:329-335

Copyright American Heart Association, Inc. All rights reserved.


Summary
Primary Hypertension is a renal disease
Interplay between genetics, environment and phenotype causes hypertension
Modifiable factors in primary HTN include salt intake and obesity
Primary HTN is preventable to a large extent
Small changes in dietary and lifestyle factors can have profound changes for cardiovascular health on a
population scale.
Thank You

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